Striosomes Constrain Locomotor Vigor in Parkinson's disease and Other Movement Disorders

National Institute On Aging

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Abstract

To investigate the impact of striosomal territories on behavior, we conducted experiments using Sepw1-Cre BAC transgenic mice. We performed bilateral injections of either AAV-DIO-taCaspase3 to induce dorsal striatal striosome ablation (SA mice), or AAV-DIO-mCherry as controls, and examined whether the assessment or response to naturalistic valence contrasts is influenced by striosomes using a modified Light/Dark box (LDb). Surprisingly, we did not find any evidence supporting the notion that striosomes affect valence perception. Instead, our results revealed that striosomes play a crucial role in controlling the speed at which mice navigate between high and low anxiety zones within the LDb. While the majority of Sepw1-Cre positive striosomes are dSPNs, traditionally associated with promoting locomotion, our study showed that striosome ablation actually increased selective, valence-sensitive speed during LDb navigation. To explore the relationship between striosomal activity, valence, and speed, we conducted in vivo calcium imaging of striosomal neurons using the genetically encoded calcium indicator GCaMP6s in miniscope-mounted mice during LDb navigation. Our calcium imaging study unveiled that the activity of striosomal neurons reflects zone location, speed, and deceleration, with over half of the light-and-speed responsive neurons exhibiting a quadratic negative correlation with speed. Furthermore, chemogenetic activation of striosomal neurons led to suppressed locomotion, supporting the negative relationship between speed and a subset of striosomal neurons. These findings demonstrate, for the first time, that striosomes regulate naturalistic motor behavior and, in doing so, modulate implicit motivation in alignment with situational valence to influence speed. The insights gained from our study may hold relevance in interpreting or predicting the contribution of striosomes to disorders related to attention, mood, and motor control, including Parkinson's disease (PD). Continued investigation into striosomal modulation by diverse afferents, such as the prefrontal cortex and anxiety nucleus BNST, and the examination of striosomal impact through efferent pathways, including striosome-dendron bouquets and the lateral habenula, will be essential in comprehending the significance of striosomes in both health and disease contexts.